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Pediatric Pharmacotherapy
A Monthly Review for Health Care Professionals of the Children's
Medical Center
Volume 5 Number 7, July 1999
Cromolyn and Nedocromil in Children with
Asthma
Marcia L. Buck, Pharm.D., FCCP
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Introduction
Mechanism of Action
Indications
Use in Children
Pharmacokinetics
Adverse Effects
Dosing Recommendations
Summary
References
Literature Reviews:
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Antibiotic induced nephropathy
Carbamazepine-associated hepatorenal failure
Intravenous valproate
Ketorolac enantiomer pharmacokinetics
Lamotrigine pharmacokinetics
Magnesium in Asthma
Formulary Update
Mast cell stabilizers have been used for over a decade in the management of asthma in
the United States. These agents are most often used as part of a triple drug regimen
which includes corticosteroids and beta-adrenergic agonists to control asthma symptoms,
but may be used as single-agent therapy in exercise-induced asthma. This brief review
will focus on the use of cromolyn sodium and nedocromil in the pediatric asthmatic
population.
Mechanisms of Action
Cromolyn and nedocromil are inhaled anti-inflammatory agents. In vitro studies have
documented their efficacy in inhibiting the degranulation of mast cells. Stabilizing mast
cells prevents the release of inflammatory mediators, including histamine and SRS-A,
(slow-reacting substance of anaphylaxis), a leukotriene believed to play an important role
in triggering an asthma exacerbation. The exact mechanisms of mast cell stabilization are
not fully understood. Recent research with cromolyn has suggested that it indirectly
inhibits calcium ions from entering the mast cell and triggering release of cellular
contents.1,2
The mast cell stabilizers inhibit both the early and late phases of bronchoconstriction
induced by inhaled antigens. In clinical trials, they have been shown to be effective in
blunting the response induced by cold air, exercise, sulfur dioxide, environmental air
pollutants, and other specific antigenic challenges. Neither agent has bronchodilator,
anticholinergic, antihistaminic, or glucocorticoid activity. It is important to note that
neither agent is effective in the acute management of a patient experiencing severe
bronchoconstriction.1,2
Indications
Both cromolyn and nedocromil are approved by the Food and Drug Administration for
the prophylactic management of bronchial asthma. Cromolyn is also approved for the
prevention of exercise-induced bronchospasm and, in a nasal spray form, for allergic
rhinitis. Cromolyn is approved for children ages 2 years and older, while nedocromil is
currently only FDA-approved for children 12 and older.1,2
Use in Children
Despite the lack of full FDA-approval, both cromolyn and nedocromil have been studied
in children of all ages.3-7 Early pediatric studies documented their efficacy as single
agents compared to other standard treatments in mild to moderate asthma. More recent
studies have focused on their use in patients with more severe disease as an adjunct to
other anti-inflammatory and bronchodilator therapies.
Petersen and colleagues gave 62 children (ages 5-15 years) who were already receiving
inhaled corticosteroids, a combination of either cromolyn plus terbutaline or terbutaline
alone.3 Aerosolized cromolyn was administered in a 10 mg dose three times daily. The
corticosteroid dose was then slowly reduced until the patient became symptomatic.
Patients receiving cromolyn plus terbutaline were better able to tolerate a reduction in
their corticosteroid dose, without worsening asthma symptoms or a need to increase betaadrenergic use. At the end of the 12 week study period, only one (3.3%) of the
cromolyn-treated patients had stopped the steroid taper because of worsening symptoms,
compared to 11 patients (34.4%) in the group without cromolyn. The authors concluded
that the addition of cromolyn to a regimen including corticosteroids may allow for
significant reduction in dosage and potential steroid-associated toxicity. In children with
mild to moderate disease, cromolyn may even replace the need for chronic
corticosteroids.
The addition of nedocromil to standard asthma regimens has shown similar results. In
1993, Armenio and coworkers documented the benefits of nedocromil in a randomized,
double-blind, placebo-controlled trial in 209 children (ages 6-17 years) with asthma.4 A
nedocromil dose of 4 mg inhaled four times daily was compared to placebo by evaluating
asthma symptom diaries, pulmonary function tests, and inhaled beta-adrenergic agonist
use. At the end of the 12 week study, total symptom scores had decreased 50% from
baseline in the nedocromil group compared to only 9% in the control group. Significant
differences were also noted in pulmonary function testing and in the reliance on
bronchodilators in the study subjects, when compared to the placebo group.
There are several papers documenting the efficacy of mast cell stabilizers in the
prevention of exercise-induced asthma in children. In 1994, de Benedictis and colleagues
from the University of Perugia performed a double-blind placebo-controlled crossover
trial to compare the efficacy of cromolyn and nedocromil in exercise-induced asthma.5
Both drugs and placebo were delivered by metered dose inhaler. Seventeen children
(ages 7-15 years) participated. All participants were receiving other medications for their
asthma. These other therapies were held for 12 hours prior to testing. Efficacy was
assessed by the amount of change in pulmonary function tests. A smaller decrease in
FEV1 (forced expiratory volume in 1 second) after exercise testing represented improved
tolerance. The mean and standard deviation for the maximum percentage drop in FEV1
was 27.4+17.3% for the placebo group versus 14.0+14.6% for cromolyn and 14.4+11.1%
for nedocromil.
These results demonstrate the protective effect of mast cell stabilizers on exerciseinduced decreases in lung function.
The difference between the cromolyn and
nedocromil treatment groups were not significant. The same investigators have also
found no difference in the duration of action of these two agents or in overall clinical
response using similar testing environments.6,7
Pharmacokinetics
After inhalation, less than 10% of a dose of cromolyn or nedocromil is absorbed from the
lung. Peak serum concentrations occur within 10-15 minutes of inhalation. Any
cromolyn that is systemically absorbed is rapidly excreted in the bile and urine, with a
half-life of approximately 1-2 hours. Nedocromil is also rapidly excreted, with an
estimated serum half-life of 3 hours in adults. Neither cromolyn nor nedocromil is
metabolized.1,2,8 Neither drug has been studied in children to determine pharmacokinetic
differences compared to adults.
Adverse Effects
The most frequently reported adverse effects with these agents are bronchospasm, cough,
or pharyngeal irritation following inhalation. In clinical trials, these reactions occurred in
5-10% of patients. Other adverse effects include laryngeal edema, nasal congestion,
wheezing, dizziness, and headache, all occurring in 1-2% of patients. Nausea and
vomiting may occur in those patients who swallow a significant part of dose for
inhalation.1,2,9,10 In addition to these more common adverse effects, there are three
reports of dysuria with cromolyn use, related to excessive systemic drug absorption.9
Hypersensitivity reactions to mast cell stabilizers occur in less than 1% of patients
treated. IgE-mediated reactions have been documented with both cromolyn and
nedocromil, with patients developing a rash, urticaria, or angioedema. Cases involving
more severe immune responses, including pulmonary eosinophilic infiltrates and allergic
granulomatosis, have also been reported with cromolyn use. 11,12
Dosing Recommendations
Cromolyn is available in two forms for the management of asthma: a 10 mg/ml solution
for nebulization and an aerosol for inhalation that delivers 800 mcg per spray. Patients
receiving cromolyn should begin therapy with 20 mg (nebulized) or 2 sprays (by aerosol)
inhaled 4 times daily for prophylaxis. Patients with exercise-induced asthma should
inhale 20 mg (nebulized) or 2 sprays (by aerosol) within 1 hr prior to exercise. Children
less than 6 years of age may respond to lower doses.1
Nedocromil is available in an aerosol dosage form which provides 1.75 mg per actuation.
The recommended dose is 2 inhalations 4 times daily at regular intervals for prophylaxis.
Some patients can achieve satisfactory effects with reduced dosing, using nedocromil
only 2 to 3 times daily.2
Patients receiving either of these agents should be instructed that these agents are not
effective for acute asthma exacerbations. In order to gain the most benefit from mast cell
stabilizers in managing asthma, these agents must be taken on a regular basis, even when
the patient is asymptomatic. Parents of young children should be instructed on how to
administer the drug to their children and methods for cleaning and storing the aerosol or
nebulizer equipment.
Symptomatic improvement typically occurs within 4 weeks of initiating therapy with a
mast cell stabilizer. Outcome also may be assessed by the ability to reduce the dose of
other asthma therapies associated with more significant dose-related adverse effects, such
as steroids, beta-adrenergic agonists, or methylxanthines.
Summary
Mast cell stabilizers are useful adjuncts to therapy with corticosteroids and betaadrenergic agonists in children with asthma. Both cromolyn and nedocromil
have little systemic absorption after inhalation and are well tolerated. These
agents may provide better control of asthma symptoms in children and allow a
reduction in the doses of therapies with more significant adverse effects.
References
1. Cromolyn sodium. In: Olin BR ed. Drug Facts and Comparisons. St. Louis:
Facts and Comparisons, Inc., 1999:182h-183a.
2. Nedocromil sodium. In: Olin BR ed. Drug Facts and Comparisons,. St.
Louis: Facts and Comparisons, Inc., 1999:183b-e.
3. Petersen W, Karup-Pedersen F, Friis B, et al. Sodium cromolycate as a
replacement for inhaled corticosteroids in mild-to-moderate childhood asthma.
Allergy 1996;51:870-5.
4. Armenio L, Baldini G, Badare M, et al. Double blind, placebo controlled study of
nedocromil sodium in asthma. Arch Dis Child 1993;68:193-7.
5. de Benedictis FM, Tuteri G, Bertotto A, et al. Comparison of the protective
effects of cromolyn sodium and nedocromil sodium in the treatment of exerciseinduced asthma in children. J Allergy Clin Immunol 1994;94:684-8.
6. de Benedictis FM, Tuteri G, Pazzelli P, et al. Cromolyn versus nedocromil:
duration of action in exercise-induced asthma in children. J Allergy Clin Immunol
1995;96:510-4.
7. de Benedictis FM, Tuteri G, Pazzelli P, et al. Combination drug therapy for the
prevention of exercise-induced asthma in children. Ann Allergy Asthma Immunol
1998;80:352-6.
8. Moss G, Jones K, Ritchie J, et al. Plasma levels and urinary excretion of
disodium cromolycate after inhalation by human volunteers. Toxicol Appl
Pharmacol 1971;20:147-56.
9. Lester MR, Bratton DL. Adverse reactions to cromolyn sodium: patient report and
review of the literature. Clin Pediatr 1997;36:707-10.
10. Foulds RA. An overview of human safety data with nedocromil sodium. J Allergy
Clin Immunol 1993;92:202-4.
11. Lobel H, Machtey I, Eldror M. Pulmonary infiltrates with eosinophilia in an
asthmatic patient treated with disodium cromolycate. Lancet 1972;2:1032
(letter).
12. Burgher L, Kass I, Schenken J. Pulmonary allergic granulomatosis: a
possible drug reaction in a patient receiving cromolyn sodium. Chest
1974;66:84-6.
Literature Review
Antibiotic-induced nephropathy
This extensive review covers the antibiotics commonly used in the neonatal period and
their potential for inducing renal dysfunction. The authors discuss well-known
nephrotoxins such as aminoglycosides and vancomycin, as well as less frequently
reported causative agents such as the beta-lactams. A thorough description of the
mechanisms for drug-induced nephrotoxicity is also included. Fanos V, Cataldi L.
Antibacterial-induced nephrotoxicity in the newborn. Drug Safety 1999;20:245-67.
Carbamazepine-associated hepatorenal failure
A 6 year-old boy receiving carbamazepine for partial seizure disorder who developed
acute hepatic and renal dysfunction is described in this report. The patient had been
receiving carbamazepine (40 mg/kg/day) for approximately 3 months prior to this event.
He was admitted with symptoms of lethargy and increased seizure frequency. Laboratory
values on admission revealed a blood urea nitrogen (BUN) of 67 mg/dl and a serum
creatinine of 3 mg/dl. Liver function tests were all significantly elevated. A
carbamazepine serum concentration at presentation was 17.7 mcg/ml, despite having
missed two doses. Carbamazepine was discontinued and the patient recovered over a
period of two weeks. Anticonvulsant therapy was switched to lamotrigine. This case,
while not the first to describe these adverse effects, is useful reminder of the ability of
carbamazepine to cause both hepatic and renal toxicity. Haase MR. Carbamazepineinduced hepatorenal failure in a child. Pharmacotherapy 1999;19:667-71.
Intravenous valproate
Three cases are presented in this article to highlight the utility of the intravenous dosage
formulation of valproate in children with status epilepticus. The authors also performed a
pharmacokinetic analysis of serum valproate levels in two of the children. Following a
loading dose of 20 mg/kg, a maintenance infusion of 4-6 mg/kg/hr provided serum
concentrations from 66-92 mg/L, within the therapeutic range. Mean apparent volume of
distribution was 0.29 L/kg, with a clearance of 63-66 ml/hr/kg. The authors suggest that
initial dosing should reflect prior exposure to anticonvulsants which induce hepatic
enzymes: 1 mg/kg/hr in patients without prior drug exposure, 2 mg/kg/hr in patients on
prior inducer therapy, and 4 mg/kg/hr in patients currently receiving high-dose
pentobarbital. Hovinga CA, Chicella MF, Rose DF, et al. Use of intravenous valproate in
three pediatric patients with nonconvulsive or convulsive status epilepticus. Ann
Pharmacother 1999;33:579-84.
Ketorolac enantiomer pharmacokinetics
Ketorolac is supplied as a 1:1 mixture of enantiomers, although almost all of the
pharmacologic activity comes from the S form. In this study, the metabolism of the R and
S enantiomers of ketorolac were evaluated in 50 children, ages 3 to 18 years. The S form
was present in lower concentrations than the R form at all time points sampled. The
elimination half-life of the S form was also shorter than the R form. For comparison, the
mean half-life of racemic ketorolac in the children studied was 4.0 hours (similar to the R
form), while the mean half-life for the S form was only 2.1 hours. The results of this
study are similar to data previously reported in adults. They suggested that the duration
of drug effect may be significantly shorter than that expected from studies of racemic
ketorolac alone. Kauffman RE, Lieh-Lai, MW, Uy HG, et al. Enantiomer-selective
pharmacokinetics and metabolism of ketorolac in children. Clin Pharmacol Ther
1999;65:382-8.
Lamotrigine pharmacokinetics
Twelve children receiving lamotrigine were evaluated to determine population
pharmacokinetic parameters. This study is unique in that none of the children were
receiving other anticonvulsants known to influence lamotrigine metabolism. Each patient
received a single dose of 2 mg/kg lamotrigine by mouth. Mean volume of distribution
was 1.50+0.51 L/kg and clearance was 0.64+0.26 ml/min/kg. When normalized for
weight, these values were found to be higher than those previously reported for adults.
Elimination half-life averaged 32 hours in the children, similar to adult values. The
authors conclude that higher doses may be needed in children than in adults to achieve
adequate serum concentrations. Chen C, Casale EJ, Duncan B, et al. Pharmacokinetics of
lamotrigine in children in the absence of other antiepileptic drugs. Pharmacotherapy
1999;19:437-41.
Magnesium in Asthma
The case of a 12 year old child given intravenous magnesium sulfate after failing
conventional therapy for the treatment of an asthma exacerbation is presented in this brief
report. A concise, but thorough, review of the medical literature related to the use of
magnesium in asthma is also provided. This short article would be a useful addition to
the files of any pediatric practitioner. Dib JG, Engstrom FM, Sisca TS, et al. Intravenous
magnesium sulfate treatment in a child with status asthmaticus. Am J Health-Syst
Pharm 1999;56:997-1000.
Formulary Update
The following actions were taken by the Pharmacy and Therapeutics Committee at their
meeting on 6/25/99:
1. Trovafloxacin (oral) and alatrofloxacin (intravenous) were removed from the
formulary. Trovafloxacin, a fluoroquinolone antibiotic, has been associated with
over 100 cases of hepatic toxicity, according to reports from the Food and Drug
Administration. Fourteen cases of acute hepatic failure have been reported,
including 6 patient deaths.
2. Modafinil (Provigil ; Cephalon) was added to the formulary. This drug is an
analeptic used in the treatment of narcolepsy. Modafinil is restricted to out-patient
use only.
3. Amprenavir (Agenerase ; Glaxo-Wellcome) was also added to the formulary.
Amprenavir is a protease inhibitor used in combination with other antiretroviral
agents in the treatment of HIV infection. The dose for adults and adolescents (1316 years of age) is 1,200 mg twice daily. The dose for children 4-12 years of age
or patients < 50 kg is 20 mg/kg twice daily or 15 mg/kg three times daily for the
capsules. An oral solution is also available for children with a recommended dose
of 22.5 mg/kg twice daily or 17 mg/kg three times daily. The difference in dosing
recommendations reflects the reduced bioavailability of the oral liquid.
Contributing Editor: Marcia L. Buck,
PharmD
Editorial Board: Anne E. Hendrick,
PharmD
Michelle W. McCarthy, PharmD
Production manager: Stephen M.
Borowitz
If you have any comments or would
like to be on our mailing list, please
contact Marcia Buck by mail at Box
274-11, University of Virginia
Medical Center, Charlottesville, VA
22908 or by phone (804) 982-0921,
fax (804) 982-1682, or e-mail to
[email protected].
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All contents copyright (C) 1995, Stephen M. Borowitz, M.D., Children's Medical
Center, University of Virginia. All rights reserved. Last Revised: September 4,
1999